Synthesis and anticonvulsant activity of 3H-imidazo[4,5-c]-pyridazine, 1H-imidazo[4,5-d]pyridazine and 1H-benzimidazole analogues of 9-(2-fluorobenzyl)-6-methylamino-9H-purine

The 3H-imidazo[4,5-c]pyridazine, 1H-imidazo[4,5-d]pyridazine, and 1H-benzimidazole analogues of the potent anticonvulsant purine 9-(2-fluorobenzyl)-6-methylamino-9H-purine (1, 78U79) were synthesized and tested for anticonvulsant activity. The 3H-imidazo[4,5-c]pyridazines 8 and 9 were prepared in five stages from 3,4,5-trichloropyridazine (2) . The 1H-imidazolo[4,5-d]pyridazine 15 was synthesized in four stages from 5-[(benzyloxy)methyl]-1,5-dihydro-4H-imidazo[4,5-d] pyridazin-4-one (10a) . The benz-imidazole analogues 18 and 20 were prepared from 2,6-dinitroaniline in three stages. These compounds were one-tenth or less as active as 1 in protecting rats against maximal electroshock-induced seizures.     

7-(2-fluorobenzyl)-4-(substituted)-7-H-imidazo[4,5-d −1,2,3-triazines and −7H-pyrazolo[3,4-d]-1,2,3-triazines. Synthesis and anticonvulsant activity

The imidazo[4,5-d]-1,2,3-triazine and pyrazolo[3,4-d]-1,2,3-triazine analogues of the potent anticonvul-sant purine, BW 78U79 (9-(2-fluorobenzyl)-6-methylamino-9H-purine, 1 ), were synthesized and tested for anticonvulsant activity. The imidazo[4,5-d]-1,2,3-triazines 11–13 were prepared in four steps from 5-aminoimidazole-4-carboxamide (2) and the pyrazolo[3,4-d]-1,2,3-triazines 18–21 were synthesized starting with 5-amino-1-(2-fluorobenzyl)pyrazole-4-carbonitrile (14) . The intermediate 1,2,3-triazin-4-ones 6 and 16 were converted to the 4-substituted targets via the 4-(4-dimethylaminopyridinium) salts 10 and 17 . Imidazotriazine 11 had potent anticonvulsant activity against maximal electroshock-induced seizures, but its propensity to cause emesis precluded further development.     

Synthesis of nucleoside analogs of 1,4-oxathiane, 1,4-dithiane,and 1,4-dioxane

The two regioisomers 6-chloro-9-(1, 4-oxathian-3-yl)-9H-purine ( 5 ) and 6-chloro-9-(1,4-oxathian-2-yl)-9H-purine ( 6 ) were obtained when 3-acetoxy-1,4-oxathiane ( 3 ) was subjected to the acid-catalyzed fusion procedure; compound 3 was prepared by a Pummerer reaction with 1,4-oxathiane 4-oxide ( 2 ). The nucleoside analog 6 could he converted into the adenine derivative 7 and 9-(1,4-oxathian-2-yl)-9H-purine-6(1H)thione ( 8 ). The following nucleoside analogs have also been synthesized: 6-chloro-9-(1,4-dithian-2-yl)-9H-purine ( 13 ), 9-(1,4-dithian-2-yl)adenine ( 14 ), 9-(1,4-dithian-2-yl)-9H-purine-6(1H)thione ( 15 ), and 6-chloro-9-(1,4-dioxan-2-yl)-9H-purine ( 18 ).     

Synthesis of 1, 5- and 1, 7-dichloro-9H-thioxanthen-9-ones

1, 5-Dichloro-9H-thioxanthen-9-one ( 2 ) was prepared by cyclization of 2-chloro-6-[(2-chlorophenyl)thio]-benzoic acid ( 10 ) obtained from 2-chloro-6-iodobenzoic acid ( 9 ) and 2-chlorobenzenethiol. Similarly, 1, 7-di-chloro-9H-thioxanthen-9-one ( 6 ) was prepared from 9 via 2-chloro-6-[(4-chlorophenyl)thio]benzoic acid ( 11 ). Compound 6 was also obtained by condensation of 2-chloro-6-mercaptobenzoic acid ( 12 ) with chlorobenzene in the presence of sulfuric acid.     

6-Substituted-9-(3-formamidobenzyl)-9H-purines. Benzodiazepine receptor binding activity

A series of 6-substituted-9-(3-formamidobenzyl)purines were synthesized and studied for benzodiazepine receptor (BZR) binding activity. Most of the target compounds were prepared by reaction of 6-chloro-9-(3-formamidobenzyl)-9H-purine ( 17 ) with the appropriate amine, alcohol or other nucleophilic reagent. Alternatively, the 6-cyclopropylaminopurine 5 was synthesized via the nitrobenzyl precursor 22 , and the 6-alkyl-thiopurines 14 and 15 were prepared by alkylation of the appropriate purine with 3-formamidobenzyl bromide. Purines with a variety of 6-substituents retained potent BZR binding properties, although certain bulky 6-substituents led to compounds with diminished activity. None of the compounds exhibited significant activity on a modified Geller-Seifter Conflict schedule.     

Synthesis of 1,8-, 1,6- and 3,6-dichloro-9H-thioxanthen-9-ones

Cyclization of 2-chloro-6-[(3-chlorophenyl)thio]benzoic acid ( 2 ) gave a mixture of 1,8-, 3 , and 1,6-dichloro-9H-thioxanthen-9-ones 4 . The mixture was converted to 1,8-diamino- 7 , and 1-amino-6-chloro-9H-thioxanthen-9-ones 8 , from which 3 and 4 were prepared separately, respectively. From a mixture of 4 and 3,6-dichloro-9H-thioxanthen-9-one ( 11 ) obtained by cyclizing 4-chloro-2-[(3-chlorophenyl)thio]benzoic acid ( 10 ) was separated 11 by conversion of 4 to 8 .     

8-Bromo-6-alkylamino-2-trifluoromethyl-9H-purines with in vitro activity against influenza a virus

Several derivatives of 8-bromo-6-dimethylamino-2-trifluoromethyl-9H-purine ( 1 ) were synthesized for structure-activity relationship studies of anti-influenza A virus activity. The 8-bromopurines were prepared by reaction of the anion of the 6-alkylamino-2-trifluoromethylpurines with N-bromosuccinimide. Several compounds had anti-influenza activity comparable to ribavirin, but no in vivo activity was observed.     

Synthesis and tautomerism of ethyl 2-(2-benzothiazolyl)-2-(6-purinyl)acetate and related compounds

Reaction of 6-chloro-9H-(2-tetrahydropyranyl)purine ( 2d ) with the sodium salt of ethyl benzothiazole-2-ace-tate ( 1 ) in dimethylformamide effects condensation of the two compounds (with loss of sodium chloride) to give the corresponding ethyl diarylacetate 4 (35%), present largely as an enol chelate tautomer. Isolated as a by-product is 6-(2-aminophenyl-1-thio)-9H-(2-tetrahydropyranyl)-purine (4%), formed via opening of the thiazole ring. Removal of the tetrahydropyranyl protective group from 4 occurs by treatment with p-toluenesulfonic acid in aqueous ethanol to produce ethyl benzothiazole-2-(6-purinyl)acetate (80%), existent largely as two enol chelate isomers. Spectral data for the various products are presented. An attempt to use 6-chloro-9-acetyl-9H-purine in place of 2d in the first reaction gives acetylation of 1 instead of condensation.     

Synthesis of 3H-pyrazol-3-one derivatives containing a 9H-thioxanthene ring

2,4-Dihydro-5-methyl-2-phenyl-4-(9H-thioxanthen-9-yl)-3H-pyrazol-3-one ( 3 ) was prepared by condensing 9H-thioxanthen-9-ol ( 1 ) with 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one ( 2 ), or by cyclizing ethyl α-acetyl-9H-thioxanthene-9-acetate ( 4 ) with phenylhydrazine. 2,4-Dihydro-5-methyl-2-phenyl-4-(9H-thioxan- then-9-yl)-3H-pyrazol-3-one 10,10-dioxide ( 8 ) was prepared by cyclizing ethyl α-acetyl-9H-thioxanthene-9-acetate 10,10-dioxide ( 7 ) with phenylhydrazine. Compound 8 was also obtained by oxidizing 3 with hydrogen peroxide in acetic acid. 5-Amino-2,4-dihydro-2-phenyl-4(9H-thioxanthen-9-yl)-3H-pyrazol-3-one ( 10 ) was obtained by condensing 1 with 5-amino-2,4-dihydro-2-phenyl-3H-pyrazol-3-one ( 9 ).     

[f]-Fused purine-2,6-diones: Synthesis of new [1,3,5]- and [1,3,6]-thiadiazepino-[3,2-f]-purine ring systems

Summary 6-Phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,8,9-hexahydro-[1,3,5]-thiadiazepino-[3,2-f]-purine (5) was obtained by a three-step synthesis from 8-mercapto-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1) and 2-(benzoylamino)-ethyl chloride (2)via 8-(benzoylaminoethylthio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (3) and its chloromido derivative4. The analogous 9-phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,6,7-hexahydro-[1,3,6]-thiadiazepino-[3,2-f]-purine (7) was synthesized either from compound1 and N-(2-chloroethyl)-benzimido chloridevia N-(chloroethyl)-S-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-7H-purin-8-yl)-benzothioimide (6), or alternatively from 7-(2-benzoylaminoethyl)-8-bromo-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (9), its 8-mercapto derivative10 and the corresponding chloroimido compound11 being the intermediates.Part of this paper was presented as a preliminary report at the Congress of Czech and Slovak Chemical Societies, Olomouc, Czech Republic, September 13–16, 1993     

Synthesis of New Nucleosides by coupling of chloropurines with 2- and 3-deoxy derivatives of N-methyl-D-ribofuranuronamide

The synthesis of new deoxyribose nucleosides by coupling chloropurines with modified D -ribose derivatives is reported. The methyl 2-deoxy-N-methyl-3-O-(p-toluoyl)-α-D -ribofuranosiduronamide (α-D - 8 ) and the corresponding anomer β-D - 8 were synthesized starting from the commercially available 2-deoxy-D -ribose ( 1 ) (Scheme 1). Reaction of α-D - 8 with the silylated derivative of 2,6-dichloro-9H-purine ( 9 ) afforded regioselectively the N⁹-(2′-deoxyribonucleoside) 10 as anomeric mixture (Scheme 2), whereas β-D - 8 did not react. Glycosylation of 9 or of 6-chloro-9H-purine ( 17 ) with 1,2-di-O-acetyl-3-deoxy-N-methyl-β-D -ribofuranuronamide ( 13 ) yielded only the protected β-D -anomers 14 and 18 , respectively (Scheme 3). Subsequent deacetylation and dechlorination afforded the desired nucleosides β-D - 11 , β-D - 12,15 , and 16 . The 3′-deoxy-2-chloroadenosine derivative 15 showed the highest affinity and selectivity for adenotin binding site vs. A₁ and A_2A adenosine receptor subtypes.     

The synthesis of 1H-benzimidazole derivatives containing a 9H-xanthene or 9H-thioxanthene ring

2-(9H-Xanthen-9-ylmethyl)-1H-benzimidazole ( 2a ) was prepared by condensing 9H-xanthene-9-acetic acid ( 1a ) with 1,2-benzenediamine. Similarly, 2-(9H-thioxanthen-9-ylmethyl)-1H-benzimidazole ( 2b ) and its S,S-dioxide ( 2d ) were obtained. Compound 2d was also prepared by oxidizing 2b with hydrogen peroxide in acetic acid. Heating of 9H-thioxanthene-9-acetic acid 10-oxide ( 1c ) with 1,2-benzenediamine gave 9-methylene-9H-thioxanthene ( 3 ). 2-(9H-Thioxanthen-9-ylmethyl)-1H-benzimidazole S-oxide ( 2c ) was obtained by oxidizing 2b with m-chloroperbenzoic acid in acetone.     

Synthesis of α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetic acid derivatives

α-(Aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate, 3 and 8 , have been synthesized by catalytic hydrogenation of 6-cyanomethylene-9-methoxymethylpurine derivatives 2 and 7 which were obtained by the substitution of 6-chloro-9-(methoxymethyl)purine ( 1 ) with α-cyanoacetamide and ethyl cyanoacetate, respectively. Substitution of 3 and 8 with amines gave the corresponding N-substituted α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate 4 and 10 . Reaction of 3 with piperidine gave 9-(methoxymethyl)-9H-purine-6-acetamide ( 5 ).     

Regioselective Sonogashira cross-coupling reactions of 6-chloro-2,8-diiodo-9-THP-9H-purine with alkyne derivatives

Lithiation of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine with LiTMP, gave access to 6-chloro-2,8-dihalogenated purine derivatives. In particular, the 6-chloro-2,8-diiodopurine derivative is an interesting new intermediate which gave regioselectively various 2-alkynylated compounds or 2,8-dialkynylated purines by using an excess of alkyne.     

Synthesis of 2-(β-D-ribofuranosyl)[1,3,5]triazines

The synthesis of the first [1,3,5]triazine carbon linked nucleosides are reported. 4-Amino-6-(β-D-ribofuranosyl)[1,3,5]triazin-2(1H)-one ( 8 ), an analog of 5-azacytidine and pseudoisocytidine was prepared. 2,5-Anhydro-D-allonamidine hydrochloride ( 3 ) was condensed with dimethyl cyanoiminodithiocarbonate ( 4 ) to give 4-methylthio-6-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 5 ). Compound 5 was reacted with m-chloroperbenzoic acid to give 4-methylsulfinyl-6-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 6 ). Displacement of the methyl sulfinyl with the appropriate nucleophile gave 6-(β-D-ribofuranosyl)[1,3,5]triazine-2,4-diamine ( 7 ), 4-amino-6-(β-D-ribofuranosyl)[1,3,5]triazin-2(1H)-one ( 8 ), and 4-amino-6-(β-D-ribofuranosyl)[1,3,5]triazine-2(1H)-thione ( 9 ). Dethiation of compound 5 with Raney nickel gave 4-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 10 ). The crystal structure of 7 was determined by single crystal X-ray.     

The synthesis of 6-C-substituted 9-methoxymethylpurine derivatives

6-Cyanomethylene ( 2 ), which was prepared via 1 by substitution with malononitrile, has been catalytically hydrogenated to the α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetonitrile ( 3 ) in good yield using N,N-dimethylformamide-benzene as solvent over Pd-C under medium pressure. Intermediate 3 was derived to aldehyde 5 by hydrolysis with acid or base. Substitution of 3 with amines gave the corresponding alkylamines 6 and 7 . Reaction of 3 with hydrazine and acetamidine hydrochloride gave pyrazole derivative 8 and pyrimidine derivative 9 , respectively.     

A convenient synthesis of tricyclic purine derivatives

A convenient synthesis of new heterocycles such as 7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-ones ( 2 , n = 0) and 5,6-dihydro-1H-imidazo[2,1-b]purin-9(8H)-ones ( 3 ) was described. The syntheses of 2 and 3 were accomplished by treatment of 6-methylthio-7H-purin-2(3-H)-ones 7 or 2-benzylthio-1-methyl-9-triphenylmethyl-9H-purin-6(1H)-one ( 15 ) with appropriate aminoalcohol followed by dehydrative cyclization using thionyl chloride. Compound 15 was efficiently prepared by benzylation of 6-hydroxy-2-mercaptopurine ( 12 ) followed by tritylation and N-methylation.     

Synthesis of 3,3′-(1,6-hexanediyl)bis-pyrimidine derivatives and 3,4-dithia[6.6](1.3)pyrimidinophane

Several 3,3′-(1,6-hexanediyl)bis[6-methyl-2,4(1H,3H)-pyrimidinedione] derivatives ( 4a, 4b , and 4c ) were synthesized from 1,6-(hexanediyl)bis[6-methyl-2H-1,3-oxazine-2,4(3H)-dione] (3) . Compound 4c was converted to 6, which reacted with thiourea giving thiuronium salt 7 . 3,3′-(1,6-Hexanediyl)bis [1-(2-mercaptoethyl)-6-methyl-2,4(1H,3H)-pyrimidinedione] (9) was obtained by the hydrolysis of 7 , and then 9 was oxidized to 12,22-dimethyl-3,4-dithia[6.6] (1.3)-1,2,3,4-tetrahydro-2,4-dioxopyrimidinophane (10) .     

The synthesis of 3H-pyrazol-3-one derivatives containing a 9H-xanthene ring

2,4-Dihydro-5-methyl-2-phenyl-4-(9H-xanthen-9-yl)-3H-pyrazol-3-one ( 3 ) was prepared by the condensation of phenylhydrazine and ethyl α-acetyl-9H-xanthene-9-acetate ( 2 ), or 9H-xanthen-9-ol ( 1 ) and 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one ( 4 ). 5-Amino-2,4-dihydro-2-phenyl-4-(9H-xanthen-9-yl)-3H-pyrazol-3-one ( 6 ) was obtained by the condensation of 1 and 5-amino-2,4-dihydro-2-phenyl-3H-pyrazol-3-one ( 5 ).     

Transformation of 4-(1-dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone into methyl 2-benzoylamino-3-oxobutanoate. The synthesis of 1-substituted 4-benzoylamino-3-methyl-5(2H)-pyrazolones

Methyl 2-benzoylamino-3-oxobutanoate ( 3 ) was prepared from hippuric acid (1) which was converted with N,N-dimethylacetamide and phosphorus oxychloride into 4-(1-dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone ( 2 ) followed by hydrolysis with hydrochloric acid in methanol. Compound 3 was treated with hydrazines 4 to give 4-benzoylamino-3-methyl-1H-pyrazol-5(2H)-one ( 6a ) and its 1-substituted derivatives 6b-j . The corresponding hydrazones 5f, i, j were isolated as intermediates.